Schizophrenia

[genisi]

Good read for you Dubi, so you won't get too bored when you're back :)

Novel consortium to address shortfall in innovative medicines for psychiatric disorders

http://www.nature.com/nrd/journal/v8/n7/full/nrd2939.html

One of the first projects to be selected for funding under the European Innovative Medicines Initiative will address the challenges of developing drugs to treat schizophrenia and depression.

By Bethan Hughes

On 18 May 2009, the European Commission announced the first 15 projects of the Innovative Medicines Initiative (IMI) that have been selected to address research bottlenecks in drug development (see Nature Rev. Drug Discov. 7, 110; 2008). Three projects aim to improve predictions of drug safety, one will use pharmaco-epidemiology methods to monitor the benefits and risks of medicines, four will create training programmes and seven will address drug development challenges in six therapeutic areas.

As soon as the finer details of the contract negotiations are complete — for example, reaching agreements on intellectual property generated by each consortium — the successful projects will share 110 million euros from the European Commission and 136 million euros provided in kind by the pharmaceutical industry over 5 years.

These IMI projects are unique because, for the first time, they each bring together a wide range of pharmaceutical companies to work with an academic consortium (that could also include small- and medium-sized enterprises and patient organizations). "Many companies already have collaborations with academic consortia, so that is not new," says Tine B. Stensbøl, Divisional Director of Discovery Pharmacology Research at the pharmaceutical company Lundbeck in Denmark, and the European Federation of Pharmaceutical Industries and Associations (EFPIA) coordinator for one of the selected consortia called NEWMEDS (Novel Methods Leading to New Medications in Depression and Schizophrenia). "But what is new is that we have so many EFPIA partners joining forces and working with one academic consortium," she says.

Overall, NEWMEDS aims to address the major need for improved treatments for depression and schizophrenia. "Enormous amounts of money have been invested by industry, as well as by academia, but the outcome has been very limited," says Mihály Hajós, Associate Research Fellow at the Neuroscience Department, Pfizer Global R&D, Connecticut, USA, whose team is participating in NEWMEDS. "We need to have this collaboration between academic groups and industry to make innovative progress," he adds.

The main focus of NEWMEDS, says Stensbøl, will be on schizophrenia. "We plan to divide our project into three clusters: one, to develop better animal models; two, to generate translational technology that could help provide early indicators of efficacy, such as functional magnetic resonance imaging; and three, to develop tools to improve patient stratification."

A key advantage of NEWMEDS will be the possibility to pool clinical data and samples from several pharmaceutical companies in a novel way. "We can sit together as scientists across companies in a pre-competitive environment and openly discuss how to use different technologies and models to get useful information from the enormous data sets that we have," says Stensbøl.

A large percentage of the clinical data from patients with schizophrenia, that will be available to NEWMEDS, will come from development programmes in which the compounds were initially evaluated using animal models based on the standard 'dopamine hypothesis' of schizophrenia. This might make it more likely that such compounds will have activities similar to existing therapies, rather than representing therapeutic breakthroughs, explains Andreas Meyer-Lindenberg, Director of the Central Institute of Mental Health in Mannheim, Germany.

"One perceived cause of the lack of truly innovative therapies for schizophrenia is that we tried to figure out how the first-generation antipsychotics — which were essentially found by serendipity — worked, and then used animal models based on that understanding to screen new compounds. Arguably, this has contributed to every approved antipsychotic so far also having dopamine D2 receptor-blocking activity: we have been looking under the lamp post for the keys because that's where the light shines," he says.

Stensbøl still considers that the clinical data collected could be valuable, however. "There's no reason not to believe that the dopamine system has, at least for some patients, an impact on schizophrenia. We need to learn from that and dissect those data in greater detail. Rather than just throwing them away, I think we can gain a lot by using novel technology to look beyond the biology that we have focused on for many years," she says.

Nevertheless, it is widely agreed that new animal models are needed to aid the development of novel therapies. According to Professor Shitij Kapur, Head of Schizophrenia, Imaging and Therapeutics at the Institute of Psychiatry, Kings College, London, UK, there are two major unmet needs in the treatment of schizophrenia. The first is to control positive symptoms, such as hallucinations and delusions, in the long term, because some patients either do not respond to treatment, or respond initially but cannot be maintained on therapy. The second is to develop therapies that effectively address the negative symptoms (such as social withdrawal and apathy) and cognitive deficits.

To respond to these challenges, much research is needed to understand the underlying pathophysiology of the disease. Currently, says Kapur, the best clues are coming from genetics. Meyer-Lindenberg agrees: "Schizophrenia is overwhelmingly heritable, and genes are the majority of the cause. Even in depression, close to 40% of the disease risk is due to genetics," he notes.

Genome-wide association studies have identified single nucleotide polymorphisms associated with a risk of developing schizophrenia, but so far the relative risk has not been sufficient to strongly justify the development of diagnostic tests or simple animal models based on these variants. This raises the question of which genes to base animal models on. "We don't have the luxury of going after 25 candidates," says Kapur. "Fortunately, a number of copy number variations (CNVs) have now been reliably replicated in schizophrenia that increase the risk 10–15 times, so that is very hopeful. Not all patients have the same CNVs, however, but they might provide clues about pathways involved in the disease biology," he adds.

These genetic variants are also providing important research avenues for human clinical studies. "You can select people based on their genotype as healthy volunteers and know that their brain systems are biased by the genetic variant in a way that leads to its role in schizophrenia [this is known as an intermediate phenotype or endophenotype]. Then you have a much better sample in which to test new drugs in the volunteer phase," says Meyer-Lindenberg.

"This could help us to determine early signs of effectiveness of a drug treatment," says Hajós. "Once we are sure that an endophenotype has impacted animals and humans in the same way, we can evaluate if it is beneficial for a patient. Then we will have the proof of concept needed to say that it is a target we could invest in and hope that patients will benefit."

A greater knowledge of endophenotypes may also improve our understanding of the complexity of the disease. "What is becoming overwhelmingly apparent is that these disorders are very likely to arise from the inheritance of multiple susceptibility genes, and quite possibly protective genes, that interact with each other and the environment — which could include the intra-uterine environment — to produce a very complex phenotype. Currently we use the overall term 'schizophrenia', but we are almost certainly talking about a heterogeneous group of disorders that have different pathophysiologies," says Husseini K. Manji, Global Therapeutic Area Head, Neuroscience R&D, Johnson & Johnson, New Jersey, USA, who thinks that an underappreciation of the complexity of the condition has contributed to lack of progress so far.

Manji's view, and the way he thinks the field is going, is to deconstruct the illness into component parts and develop animal models that do not have to recapitulate the whole syndrome. "If we are able to map symptoms associated with specific brain circuits, and understand the synapses, connectivity and synchronous response characteristics of neuronal ensembles in those circuits, this will lead to the possibility of identifying completely novel targets. Then we can tailor drugs to those targets to address circuitry and synaptic aspects that will hopefully lead to changes in overall symptoms," he says.

This change in approach to drug development for psychiatric disorders like schizophrenia would require acceptance from regulatory agencies. "I do think that there is an increased recognition among key stakeholders that, in order to really make progress in this arena, there needs to be an increased focus on the subcomponents of the illness," says Manji, adding that optimal treatment of schizophrenia in the future is going to require a multipronged approach. "As we progress with better identification of genes, advanced imaging technology, and good biomarkers, we will be poised to do much more."